A number of studies have indicated that prolonged, major depression disorder (MDD) is associated with a selective loss of hippocampal volume that persists long after the depression has resolved. Ionotropic glutamate receptor subtypes and apoptotic cell death pathways are very likely to be involved in this process. The induction of endogenous neuronal pathways, such as those increasing BDNF levels, can prevent neuronal loss. In addition, glucocorticoids, the adrenal steroids secreted during stress, may also play a contributing role in neuron loss. The interplay of IGR activation, particularly receptors of the NMDA subtype, neurotrophin release and synthesis are critical to maintaining neuronal viability. Genetic variation in IGR genes, neurotrophin genes, and stress pathways are likely to profoundly influence neuronal viability. BDNF interacts with a receptor tyrosine kinase (TrkB), allowing for neuronal survival and synaptic strengthening. There is growing interest in the BDNF (BDNF) and the TrkB (NTRK2) genes as candidates for vulnerability to addictions and other psychiatric conditions, including anxiety and MDD. MDD shares significant comorbidity with alcoholism, although the contribution of MDD to alcoholism is not well understood. From the foregoing discussion it could be expected that BDNF variation might influence behavior. Several recent studies have looked at the relationship between the functional BDNF Val66Met variant and psychopathology in humans. The results have been conflicting. Apart from differences in study design, genotyping, and data analysis, one possibility for this lack of consensus is that other BDNF functional alleles may be present and have a role in psychopathology. Based on differential expression results and on the fact that multiple BDNF promoters direct its transcription, we used variant discovery approaches to identify two sequence variants in BDNF promoter regions and two variants in 5? untranslated exons 1 and 4. In addition, genotyping was performed in U.S. Caucasian, American Indian, and African American populations. Lifetime DSM-III-R psychiatric diagnoses were assigned and the Tridimensional Personality Questionnaire (TPQ) administered to measure anxious temperament (harm avoidance [HA]) and novelty seeking (NS). A novel SNP was discovered (nt -281) in BDNF promoter 1 with decreased DNA binding in vitro and decreased basal reporter gene activity in transfected rat hippocampal neurons. The frequency of the -281A allele was 0.03 in a Caucasian sample but was virtually absent in other populations. Single allele-based association studies in a community-based Caucasian sample showed that individuals with the -281A allele (13 heterozygotes) had lower TPQ HA (F = 4.8, p < 0.05) and were less likely to have a psychiatric diagnosis (0.69 v 0.47, ?2 = 2.4, p = 0.12). In contrast, the Met 66 allele was associated with increased HA (F = 4.1, p = 0.02) and was most abundant in individuals with both anxiety disorders and major depression (p < 0.05). In this population, the low activity ?281A allele may be protective against anxiety and psychiatric morbidity whereas Met 66 may be a risk allele.